Piperazine salt of phytic acid



United States Patent Ofifice 3,019,226 PIPERAZINE SALT F PHY TIC ACIDJack Bernstein, New Brunswick, and William A. Lott,

Maplewood, NJ., assignors to Olin Mathieson Chemical Corporation, NewYork, N.Y., a corporation of Virginia No Drawing. Filed Apr. 10, 1959,Ser. No. 805,375 1 Claim. (Cl. 260-268) This invention relates to newurolitholytic agents and more particularly to new compounds which arethe salts of phytic acid and non-toxic organic bases.

Recently it has been found that sodium phytate is of use in loweringurinary calcium, thereby reducing the incidence of kidney stones insusceptible persons. To be effective in the reduction of renal calculi,however, relatively large dosages of the medicament are required,usually in the range of about 5 grams to about 20 grams daily.Unfortunately persons who have a history of kidney stones are oftenafilicted with other physiological conditions, such as hypertension orrelated cardiac conditions, which counterindicate the ingestion of largequantities of sodium ion. Hence, sodium phytate suffers the disadvantageof requiring the administration of large quantities of sodium ions topatients from whom sodium (e.g. salt) should be kept.

It is an object of this invention, therefore, to provide a new class ofchemical compounds which are useful in the treatment and/or preventionof renal calculi and which are less likely to cause untowardside-eifects.

This object is achieved by the compounds of this invention whichcomprise the salts of phytic acid and non-toxic organic bases,preferably organic bases which yield watersoluble salts with phyticacid, such as non-toxic organic bases of less than ten carbon atoms, asexemplified by the non-toxic lower alkyl amines, di(lower alkyl) amines,hydroxy(lower alkyl)amines (e.g. p-aminoethanol and 1-amino-Z-propanol), di-hydroxy(lower alkyl)amines, trihydroxy(loweralkyl)amines (e.g. triethanolamine and triisopropanolamine), amino-loweralkanediols, amino-lower alkanepolyols (e.g. N-methyl-glucamine),hydroxy-polyalkylene-polyamines [c.g. N-(hydroxyethyl)diethylenetriamineand N-(hydroxyethyl)propylenediamine], ester and ether derivatives ofsuch hydroxy containing amines (e.g. acetylethanolamine andZ-aminoethoxyethanol), polyalkylene-polyamines (e.g.triethylene-tetramine), monocyclic N-heterocyclic compounds, such aspiperazine and 4-(aminopropyl)morpholine, and quaternary ammonium saltssuch as choline. (By salts of phytic acid and nontoxic organic bases ismeant not only salts wherein all twelve acidic hydrogen ions of thephytic acid are combined with organic bases, but also salts wherein thephytic acid is partially neutralized and salts wherein some of thephosphate groups are neutralized with inorganic bases, such as alkalimetals.)

To prepare the compounds of this invention: (a) phytic acid is reactedwith the desired non-toxic organic base to yield the fully or partiallyneutralized corresponding phytate derivative; or (b) by metathesis, aninorganic salt of phytic acid, such as an alkali metal salt (e.g. sodiumphytate) is treated with the desired non-toxic organic base or aninorganic acid-addition salt thereof (e.g. hydrochloride) to yield aphytic acid derivative fully or partially neutralized with the desirednon-toxic organic base; or (c) phytic acid is treated with an inorganicacid salt of 3,019,226 Patented Jan. 30, 1962 Q the desired non-toxicorganic base. If sodium phytate is employed as the reactant, thenpreferably all or substantially all of the sodium ion is replacedthereby minimizing the sodium content of the final phytate product.

The compounds of this invention are useful in the treatment and/orprevention of renal calculi, for which purpose they are administeredperorally in a daily dose of about 5 grams to about 20 grams. Thecompounds of this invention can be formulated in the usual manner togive peroral compositions, such as tablets, capsules or powders, or maybe suspended or dissolved in customary manner to give elixers, syrups,etc.

The following examples illustrate the invention (all temperatures beingcentigrade):

EXAMPLE 1 Phytic acid, salt with 3 moles of piperazine hexahydrate To200 cc. of a 40% aqueous solution of phytic acid is added 97 g. (0.5 M)of piperazine hexahydrate. The resulting solution has a pH of 3.7 and atotal volume of 275 cc. 100 cc. of this solution is diluted to 800 cc.(pH 4.2) and freeze-dried to yield about 39 g. of product melting atabout 90100.

EXAMPLE 2 Phytic acid, salt with 6 moles of piperazine decahydrate To200 cc. of 40% aqueous solution of phytic acid is added 194 g. (1.0 M)of piperazine hexahydrate. The solution has a pH of 7.4 and a totalvolume of 360 cc. After standing a few minutes crystallization occurs.Then 500 cc. of methanol is added and the mixture allowed to stand. Thesolid is filtered and washed with methanol to yield about 159 g. ofproduct melting at about with decomposition.

EXAMPLE 3 Phytic acid, salt with 6 moles of choline To 100 cc. of 45%aqueous solution of choline bicar bonate is added 64 cc. of a 40%aqueous solution of phytic acid. The pH of the resulting solution is 5.1and the total volume is cc. The product can be isolated by diluting 80cc. of the solution to 500 cc. with water (pH 5.3) and freeze-drying toyield a gummy solid.

EXAMPLE 4 Phytic acid, salt with p-aminoethanol To 100 cc. of a 40%aqueous solution of phytic acid is added 51.2 g. (0.84 M) ofp-aminoethanol. The pH of the resulting solution is 6.4 and the totalvolume is cc. 100 cc. of this solution is diluted to 800 cc. andfreezedried to yield the product as a viscous oil.

EXAMPLE 5 Phytic acid, salt with triethanol amine To a solution of 92.4grams of sodium phytate in 100 ml. of water, there is added a solutionof 220 grams triethanol amine hydrochloride in 500 ml. of water. Thesolution is then freeze-dried and the residue suspended in 500 ml. ofabsolute ethanol. The insoluble sodium chloride is removed by filtrationand the filtrate is concentrated to dryness under reduced pressure togive the de' sired product as a viscous oil.

3 EXAMPLE 6 Phytic acid, salt with N-methylglucamine References Cited inthe file of this patent UNITED STATES PATENTS Stoehr July 17, 1894Connstein Jan. 15, 1901 Adams et a1 Jan. 6, 1942 Karrer Mar. 18, 1952Blackett et al. Dec. 18, 1956 Petrow et al Apr. 29, 1958 Bond Dec. 29,1959

